Safety and Efficacy of 177Lutetium-PSMA-617 Radioligand Therapy Shortly after Failing 223Radium-Dichloride

Simple Summary The alpha emitter 223Radium-dichloride (223Ra) and the beta emitter 177Lutetium (177Lu) targeting the prostate-specific membrane antigen (PSMA) are sequentially used for therapy of advanced bone-metastatic castration-resistant prostate cancer. Despite routine performance in patients who had received 223Ra, it is not clear whether disease sites refractory to alpha radiation can be effectively treated with 177Lu-PSMA-617. Secondly, it remains to be elucidated if therapy with 177Lu-PSMA-617 can be safely performed shortly after 223Ra, bearing in mind the myelotoxic potential of both treatments. The aim of our retrospective study was to evaluate safety and efficacy of 177Lu-PSMA-617 within less than 8 weeks after failing 223Ra. Radioligand therapy with 177Lu-PSMA-617 shortly after failing 223Ra is effective and can result in long-standing disease control even in patients with disseminated or diffuse bone involvement. Patients with oligo- and multifocal bone metastases show significantly longer overall survival with lower risk of significant hematotoxicity compared to patients with disseminated/diffuse involvement. Abstract Bone-seeking 223Radium-dichloride (223Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with 177Lutetium-PSMA-617 (177Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of 177Lu-PSMA-617 in patients with progressive bone involvement under treatment with 223Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started 177Lu-PSMA-617 within 8 weeks after the last 223Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of 223Ra and a median of 4 (IQR 2–7) cycles 177Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first 177Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of 177Lu-PSMA-617 after failing 223Ra is effective with an acceptable toxicity profile.

Radionuclide therapy with the bone-seeking alpha emitter 223 Ra is an established treatment prolonging survival and reducing morbidity in patients with osteoblastic bone dominant disease and no visceral metastases [8]. Radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA) has been increasingly implemented in patients with metastatic castration-resistant prostate cancer (mCRPC) failing standard treatment options [9,10]. PSMA is a type II transmembrane glycoprotein, highly overexpressed in prostate cancer cells. Using small-molecule inhibitors such as PSMA-617 labeled with the beta-emitting radionuclide 177 Lutetium ( 177 Lu) allows selective radiation of PSMAexpressing cells, whilst sparing surrounding normal tissue, regardless of metastatic site.
Several published studies on RLT with 177 Lutetium-PSMA-617 ( 177 Lu-PSMA-617) included patients previously treated with 223 Ra and few studies reported the safety of 177 Lu-PSMA-617 in such patients [11][12][13]. However, no study has addressed the feasibility of 177 Lu-PSMA-617 directly after failure of 223 Ra. It is not yet clear if bone metastases refractory to 223 Ra can be effectively treated with 177 Lu-PSMA-617. Furthermore, the safety of 177 Lu-PSMA-617 immediately after 223 Ra needs to be investigated, considering the myelotoxic potential of both treatments. This study aims to assess the safety and efficacy of 177 Lu-PSMA-617 of patients with progressive bone involvement under treatment with 223 Ra starting within 8 weeks after the last 223 Ra application.

Patients
Twenty-eight men (median age 73 years, range 63-89 years) with progressive mCRPC, who started 177 Lu-PSMA-617 within 8 weeks after the last 223 Ra administration, were included in this retrospective study. Progression was assessed by bone scan routinely performed after the 3rd and the 6th cycle or in case of biochemical progression. A median of 4 (IQR 3-6) and a total of 120 cycles of 223 Ra were administered with a mean activity of 4.197 ± 0.590 MBq, and no acute renal or bone marrow toxicities were observed. Other previous treatments comprised androgen receptor signaling inhibitors (abiraterone, enzalutamide) and taxane-based chemotherapy (Table 1). Treatment initiation was approved by an interdisciplinary tumor board. General prerequisites for 177 Lu-PSMA-617 included an estimated glomerular filtration rate (eGRF) of ≥30 mL/min/1.73 m 2 , hemoglobin (Hb) ≥ 8 g/dL, a white blood cell count (WBC) ≥ 2000/µL, platelets (Plt) ≥ 75,000/µL and sufficient PSMA-expression on 68 Ga-PSMA-11 PET/CT imaging. The extent was categorized into (1) low (oligo-/multifocal, i.e., 2-20 lesions) and (2) high (disseminated/diffuse, i.e., >20 lesions). Written informed consent was given prior to each treatment cycle. Patient characteristics are depicted in Table 2. Data presented as median with interquartile range (IQR) or n (%), PSA: prostate-specific antigen.

Toxicity Assessment
Blood values (Hb, WBC and Plt), PSA and renal function based on eGFR were tested prior to each cycle, every 4 weeks throughout the treatment and every 6-12 weeks after the last cycle. Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 was used to grade hematologic adverse events. Grade ≥ 3 toxicities were denominated significant.

Data Analysis
Retrospective data analysis was approved by the local ethics committee and was carried out using SPSS (IBM SPSS Statistics 27.0, Armonk, NY, USA). The significance level of all tests was set at p < 0.05. Continuous variables are presented as median with interquartile range (IQR) or mean ± standard deviation. Categorical variables are shown as frequencies and percentages. Progression-free survival (PFS) is defined as the time interval from 177 Lu-PSMA-617 initiation until progression on molecular, PSMA-based imaging, or the onset of other systemic treatments. Overall survival (OS) is defined as the time between the initiation of radioligand therapy and death from any cause; censoring was performed if the patient was alive at the time of analysis. The Kaplan-Meier method was used to calculate PFS and OS. Cox regression analysis was used to test the association of treatment response and survival.

Response and Survival
A total of 131 treatment cycles were performed at intervals of 6 to 8 weeks. Patients received a median of four cycles (IQR 2-5) 177 Lu-PSMA-617 with a mean activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA decline of ≥50% 12 weeks after the first treatment cycle was seen in 18/28 (64.3%) patients, 7/28 (25.0%) patients showed a >25% PSA increase.
of all tests was set at p < 0.05. Continuous variables are presented as median with interquartile range (IQR) or mean ± standard deviation. Categorical variables are shown as frequencies and percentages. Progression-free survival (PFS) is defined as the time interval from 177 Lu-PSMA-617 initiation until progression on molecular, PSMA-based imaging, or the onset of other systemic treatments. Overall survival (OS) is defined as the time between the initiation of radioligand therapy and death from any cause; censoring was performed if the patient was alive at the time of analysis. The Kaplan-Meier method was used to calculate PFS and OS. Cox regression analysis was used to test the association of treatment response and survival.

Response and Survival
A total of 131 treatment cycles were performed at intervals of 6 to 8 weeks. Patients received a median of four cycles (IQR 2-5) 177 Lu-PSMA-617 with a mean activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA decline of ≥50% 12 weeks after the first treatment cycle was seen in 18/28 (64.3%) patients, 7/28 (25.0%) patients showed a >25% PSA increase.
In total, 17 out of 28 (60.7%) patients received subsequent therapies upon progression ( Table 1), 13 of whom after initial disease control (7 PR, 6 SD). They lived significantly longer than those who did not receive further life-prolonging treatment (28 vs. 12 months; p = 0.026).
All six patients with significant hematotoxicity also showed disease progression which resulted in treatment discontinuation. One out of six patients received abiraterone and re-treatment with enzalutamide and lived 11 months after the last cycle. Another patient received docetaxel and repeated transfusion therapy and lived 13 months. All other patients died within 4 months after the last treatment cycle. Characteristics of these patients are detailed in Table 5. At baseline, 15/28 (53.6%) patients showed low grade renal function impairment (grade 1/2). Moderate function decline to grade 2 was seen in 7/28 (25.0%) patients but no significant nephrotoxicity occurred.

Discussion
The rationale of systemic treatments with the bone-seeking calcium mimetic 223 Radiumdichloride and PSMA-targeting radioligand 177 Lutetium-PSMA-617 is the selective internal radiation of prostate cancer cells. Despite being a common scenario in clinical practice, only few studies focused on the outcome of 177 Lu-PSMA-617 in patients previously treated with 223 Ra and no report exists on the efficacy of RLT with 177 Lu-PSMA-617 in patients refractory to 223 Ra. The observed PFS of 10 months and OS of 18 months in this retrospective study demonstrate efficacy of RLT with 177 Lu-PSMA-617 in mCRPC patients failing 223 Ra with progressive bone metastases.
Following several retrospective studies on the value of 177 Lu-PSMA-617 in patients with mCRPC [14,20], the recently published phase III VISION study showed a significant life-prolonging effect of 177 Lu-PSMA-617 when added to standard care in patients with progressive mCRPC after exhausting at least one taxane-based chemotherapy regimen and one androgen-receptor-pathway inhibitor [9]. Patients treated with 177 Lu-PSMA-617 and standard care had a longer PFS (8.7 vs. 3.4 months, p < 0.001) and OS (15.3 vs. 11.3 months, p < 0.001) as compared to standard care alone. The influence of resistance to 223 Ra was not evaluated as patients receiving 223 Ra within 6 months of randomization were excluded.
Few reports suggested that survival outcome of patients undergoing 177 Lu-PSMA-617 may not be affected by previous exposure to 223 Ra but it is unclear if 177 Lu-PSMA-617 could produce any objective response in patients failing 223 Ra. In a recent study by Sartor et al., 26 patients receiving 1 to 6 (median 6) 223 Ra administrations 1 to 31 months (median 8 months) before the start of 177 Lu-PSMA-617 were analyzed [11]. Thirteen patients received other life prolonging treatment between 223 Ra and 177 Lu-PSMA-617. An OS of 13.2 (95% CI 8.4-16.2) months was reported but no information on response to 177 Lu-PSMA-617 and PFS was given. In another multicenter study (WARMTH), 223 Ra 1-36.4 months before the first cycle of 177 Lu-PSMA-617 had no impact on OS (10.8 vs. 11.3 months, p = 0.34) [21]. The median time interval of 3.9 months between the two treatments may be indicative of resistance to 223 Ra in some patients, but no information was given regarding the outcome of 177 Lu-PSMA-617 in patients failing 223 Ra. No further information was provided regarding the outcome of 177 Lu-PSMA in this subgroup. In our study, RLT with 177 Lu-PSMA-617 starting within 8 weeks from 223 Ra could yield long-lasting disease control (PR + SD) in 19/28 (67.9%) patients with a PFS of 12 (95% CI [11][12][13] months. This finding indicates the efficacy of 177 Lu-PSMA-617 in patients with progressive bone-metastatic mCRPC irrespective of recent resistance to 223 Ra. Disease control was also associated with a significantly longer OS (28 vs. 11 months, p < 0.001). The relatively long OS even in non-responders may be due to subsequent treatments after 177 Lu-PSMA-617 in most patients (n = 5/9) with a significant life-prolonging effect.
PSA response, defined as ≥50% PSA reduction at 12 weeks, has also been used in other studies for treatment response assessment in patients receiving 177 Lu-PSMA-617 [22,23]. In our study, PSA response showed significantly longer survival (PFS 12 vs. 6 months, p = 0.001; OS22 vs. 15 months, p = 0.047). The PSA response rate of 64.3% in our cohort is in line with results from the phase II TheraP trial showing ≥50% PSA decline after 177 Lu-PSMA-617 in 66% (65/99) of mCRPC patients previously treated with docetaxel; no information regarding previous treatment with 223 Ra and PFS in PSA responders was reported [24]. In a study by Ahmadzadehfar et al., PSA response was not significantly different between patients with no history of treatment with 223 Ra (n = 17/26; 58.6%) compared to patients treated with 1 to 6 cycles 223 Ra within up to one year (median: 11 weeks) before the start of 177 Lu-PSMA-617 (n = 9/20; 45.0%). The significance of initial PSA response (≥50% after 4 weeks) to 177 Lu-PSMA-617 as a positive predictor of outcome remains controversial. A few studies in heterogeneous patient cohorts showed a longer OS in patients with early PSA response [13,21,25], whereas other studies reported no significantly longer survival in early responders [23,26]. In a study by Leibowitz et al. on 24 elderly patients at >75 years of age, 14 of whom previously treated with 223 Ra, a PSA decline of ≥ 50% was associated with a significantly longer OS (10.9 vs. 3.1 months, p = 0.0006) [13]. In our study, patients (n = 14/28, 50.0%) with PSA response after the first cycle showed only a trend towards longer imaging-based PFS (11 vs. 7 months; p = 0.589). 223 Ra has a relatively low myelosuppressive potential, possibly owing to the short range (<100 µm) of high-energy alpha particles and its quick blood extraction [27]. In the pivotal ALSYMPCA trial, grade ≥ 3 reduction in blood parameters was observed in 13% (Hb), 6% (Plt), and 3% (WBC) of patients. Treatment with 177 Lu-PSMA-617 has a comparably low toxicity profile due to direct binding to the cell membrane and internalization, sparing the surrounding tissue [9]. Radiation exposure of 223 Ra to the kidneys is extremely low, as the major route of elimination is the bowel. 177 Lu-PSMA-617 has demonstrated low nephrotoxicity due to its rapid renal excretion. In our patients, no grade ≥ 3 nephrotoxicity occurred.
High extent of metastatic bone involvement may increase the risk of myelotoxicity and is suggested as a negative prognostic factor for survival after RLT with 177 Lu-PSMA-617. Groener et al. showed, that patients with disseminated/diffuse osseous involvement at baseline (n = 77/140) had a significantly higher incidence of hematotoxicity (OR 5.08, p = 0.04) [19]. Similarly, in a report on the subgroup of patients from the multicenter WARMTH study with known numbers of bone lesions, only patients with >20 bone lesions or diffuse bone marrow involvement developed significant thrombocytopenia (n = 18), no significant leukopenia was observed [30]. In our study, five out of six patients developing significant hematotoxicity had >20 bone lesions at baseline. Patients presenting with high bone tumor load (n = 12/28) also showed a significantly shorter OS compared to patients with low bone tumor load (p = 0.045) despite similar PFS (p = 0.701).
Our study has clear limitations. Firstly, similar to previous studies, using standard activities for all patients may be considered as a confounding factor in the evaluation of response to treatment and survival outcome. The retrospective nature of our study and the small cohort inevitably limit the strength of the results and impede extensive subgroup analysis. Moreover, patients with temporary myelotoxicity of grade ≥ 3 who recovered later than 8 weeks after the last 223 Ra treatment were not included in this analysis. Subsequent therapies contributed to longer OS; therefore, PFS may be a more appropriate surrogate for evaluation of treatment efficacy in our study.

Conclusions
RLT with 177 Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223 Ra in patients with progressive bone-metastatic mCRPC refractory to 223 Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity.